A safe therapy is needed for excitotoxic insults such as stroke, seizures and traumatic brain injury. Many studies have implicated endocannabinoid responses in neuroprotection against excitotoxicity. Endocannabinoids (e.g., anandamide) are released in response to excitotoxicity, and recent reports indicate that enhancing this on- demand action of endocannabinoids provides efficient repair signaling and a potential treatment strategy. FAAH inhibition promotes endocannabinoid responses without causing unwanted psychotrophic effects, and facilitates cellular and functional protection. Novel inhibitors will be generated through lead optimization chemistry. A convenient model to screen our new compounds will be the kainic acid (KA)-injected rat that exhibits excitotoxic seizures, indications of brain damage, and behavioral deficits. Preliminary results show that new generation inhibitors of the endocannabinoid- hydrolyzing FAAH reduce KA-induced seizure scores and excitotoxic damage, and improve performance on behavioral tasks. The in vivo protocol allows sensitive and valid assessment of compounds as we design beneficial neuroprotectants. This Phase I SBIR application will focus on the design, synthesis as well as in vitro and ex-vivo evaluation of a selective number (2-4) of representative FAAH inhibitors for enhancement of brain endocannabinoid levels. It will also evaluate the most promising compounds in vivo for molecular, cellular, and functional protection against KA-induced excitotoxic damage. Future work to be performed under Phase II of this SBIR will assess the most promising compounds for reducing seizure severity in a KA model of excitotoxicity. Subsequently, one candidate and 2 or 3 backup compounds will be identified for preclinical development. The discovery of effective FAAH inhibitors under the auspices of this project offers excellent opportunities for the development of novel therapeutic medications for brain injury and neurodegenerative diseases such as Parkinson's and Alzheimer's. [unreadable] [unreadable] [unreadable]